Method for preparing pregnenones



United States Patent IVIETHOD FOR PREPARING PREGNENONES Monroe E. Wall,Oreland, Pa., assignor to the United States of America as represented bythe Secretary of Agriculture 13 Claims. (Cl. 260-3975) (Granted underTitle 35, US. Code (1952), sec. 266) A non-exclusive, irrevocable,royalty-free license in" the invention herein described, throughout theworld forall purposes of the United States Government with power togrant sublicenses for such purposes, is hereby granted to the Governmentof the United States of America.

This application is a continuation-in-part of co pending applicationentitled Isosapogenins, filed June 30, 1953, Serial Number 440,571, nowabandoned, and is a division of Patent No. 2,805,221.

This invention relates to -isosapogenins, to methods for preparation ofsuch compounds, and to processes for converting them into pregnenonesand other useful steroidal compounds.

Steroidal sapogenins constituted a small, well known class of steroidsobtained by the hydrolysis of their natmones and other valuable steroidderivatives.

urally occurring glycosides and having the basic structure shown below.

" All known steroidal sapogenins have the same basic structure butdiffer in several ways. For example, addi- Treatment of steroldalsapogemns with acetic anhydrrde at about 200 C. for several hours opensthe F-ring and yields pseudosapogenin diacetates. These on hydrolysisyield pseudosapogenins. These reactions and products 2,902,496 PatentedSept. 1, 1959 are well known. The formula of pseudosarsasapogenin, atypical example, is the following:

It is well known that treatment of pseudosapogenins with hothydrochloric acid regenerates the F-ring and yields the originalsapogenin. It is also known that treatment of the pseudosapogenins withCrO in acetic acid yields pregnenones useful in the production of sexhor- While these reactions have been used to convert steroidalsapogenins into pregnenones, they are not satisfactory be cause of thelow yields obtained and the diificulties encountered in purifying theproducts. The pseudosapm genins are rather unstable and are particularlyditficult to isolate and purify. Consequently, the usual practice hasbeen to make no attempt to isolate them but rather to' oxidize them inthe reaction mixture in which they were formed. This has resulted inpregnenones being formed in grossly contaminated and intractablereaction mixtures from which they could be recovered only by tediousprocedures resulting in low yields.

An object of this invention is to provide new and useful steroidalsapogenin derivatives; another object is to provide improved processesfor converting steroidal sapogenins into new compounds that are readilyisolated and purified and are also readily converted into pregnenonesand other valuable steroid derivatives. Still an other object is toprovide new and improved processes for the production of pregnenones.

According to the invention, any steroidal sapogenin may be converted tothe isomeric 20-isosapogenin and the latter in turn may be oxidized to apregnenone. The sapogenin is first converted to the correspondingpseudosapogenin by any known process. The pseudosapogenin or thereaction mixture containing it, is then treated with weak acid atsubstantially room temperature whereby it is converted to theZO-isosapogenin. The 20-isosapogenius are readily isolated and purifiedand are extremely useful as intermediates for the synthesis of sexhormones and other steroidal compounds. Thus, they are readily oxidizedto pregnenones by the same procedures used to oxidize pseudosapogeninsto pregnenones. The most commonly used procedure is to treat with asolution of (Ero in acetic acid, though other variants are known. Thepregnenones thus obtained are identical with those obtained by theoxidation of the pseudosapogenins but are obtained in higher yield andgreater purity. The reactions are illustrated below, smilag enin beingtaken as a typical example of a sapogenin.

Anhydride .1 Smilagenin IV 16-pregnen-3,20-dione GrO K By comparingFormulas I and III, above, it will be seen that the natural sapogeninsand the isosapogenins of this invention are identical except for theconfiguration at C2 Examination of molecular models of these twoisomeric compounds shows that the E-ring of the'iso compounds is highlystrained. It is believed that :this strained configuration accounts forthe greater reactivity of the iso compounds, particularly theirsusceptibility to oxidation. The natural sapogenins are inert to theconventional CrO oxidation used to convert pseudosapogenius topregnenones. In contrast, the 20-isosapogenins are readily cleaved byCrO yielding 20-keto-l6-pregnenes.

The invention 'is more fully illustrated by the following examples.

EXAMPLE I was thus formed and was filtered out, washed with water anddried. The product (9.0 g.) was recrystallized from methanol.

EXAMPLE II p .Ten grams of pseudosmilagenin, obtained from smila- .geninby conventional procedures, were dissolved in 200 ,ml. of absoluteethanol. To this solution 200 ml; of glacial acetic acid were added andthe mixture was left r -Cl II Smilagenin diacetate KOH, Acetic acid n k-36 H III 20-isosmi1agenin overnight at room temperature. Dilution withwater then precipitated 20-isosmilagenin having the formula Five gramsof ZO-isosarsasapogenin were dissolved in 150 ml. of glacial aceticacid. To this was added dropwise, with stirring a solution .of 5 g. ofCrO in acetic acid in water, the temperature being held at 15 C. Afterthe solutions had been mixed and held 1 hour at room temperature, theproduct was extracted with ether. The ether solution was thoroughlywashed with water, after which the ether was removed by evaporation. Theresidue was dissolved in tert.-butanol containing 5 g. of KOH dissolvedin 10 ml. of water. This 2-phase mixture was stirred at room temperaturefor 3 hours. Dilution with water and extraction with ether then yielded60% of the theoretical amount of 16-pregnen-3,20-dione. v

EXAMPLE IV Ten grams sarsasapogenin were heatedwith 20ml. acetic,anhydride at 200 .C. for 10 hours. The-aceticanhydride was evaporatedin vacuo and the residue ,refluxed with 20 grams KOH-in 200 m1.methanol. -,An excess of glacial .acetic acid was then added and afterstanding overnight, water was added and the crude 20.-.isosarsasapogenin filtered off. This was then oxidized to 16 pregnen-3,20 dione as in Example III. 7 Similar oxidation of ZO-isosmilagenin,20-isotigogenin ,and 20-isoheco genin yielded respectively 16- pregnen3,

20-dione, 16-allopregnen-3, 20-dione, l6-allopregnen-3,12, 20-trione.

In accordance with the foregoing examples, 20-isodiosgenin,20-isotigogenin, and ZO-isohecogenin, having the followingconfiguration, were also produced:

io-i's'odiosgenin,

ZO-isotigogenin, and

I ll ZO-isohecogenin.

The characteristics of these compounds are given in Table I, below.

For converting pseudosapogenins to 20-isosapogenins almost any acid maybe used. If a strong acid is used it must be highly diluted. On theother hand, if a weak acid is used it may be used in almost anyconcentration. Heat is not essential and, when using any but a very weakacid, is detrimental.

The great advantage of making the 20-isosapogenins as intermediates inthe conversion of sapogenins to pregnenones is that they are easilyisolated and purified, and the subsequent oxidation step gives higheryields and more readily purified products when starting with a pure 20-isosapogenin than when starting with a reaction mixture containing crudepseudosapogenin.

Table l OBSERVED PROPERTIES OF ZO-ISOSAPOGENINS 1. A process forproducing a 20-keto-16-pregnene which comprises oxidizing a steroidal20-isosapogenin selected from the group consisting of 10 and with CrOand recovering the thus formed -keto-16- pregnene.

2. A process as in claim 1 wherein the 20-isosapogenin is20-isosarsasapogenin having the formula 3. A process as in claim 1wherein the 20-isosapogenin is 20-isotigogenin having the formula 4. Aprocess as in claim 1 wherein the 20-isosapogenin is ZO-isosmilageninhaving the formula 5. A process as in claim 1 wherein the20-isosapogenin is 20-isohecogenin having the formula H CHELZO HO I H 6.A process as in claim 1 wherein the 20-isosapogenin isZO-is'odiosgenin'having the'formu'la 7. A process for producing a20-keto-l6-pregnene whidh comprises heating anatural steroidal sapogeninwith acetic anhydride to produce a first reaction mixture containing thecorresponding pseudosapogenin, treating said first reaction mixture withweak acid at substantially room temperature to produce a second reactionmix- Iurecontaining a steroidal 20-isosapogenin selected from 20 thegroup consisting of and oxidizing said 20-isos'apogenin contained insaid second reaction mixture with (3103 to produce the corresponding20-keto-l6-pregnene, and recovering said 20-keto-l6- pregnene from theoxidized second reaction mixture.

8. A process as in claim 7 wherein the weak acid is an 13. A process asin claim 7 wherein the sapogenin is diosgenin.

References Cited in the file this patent UNITED STATES PATENTS MarkerJuly 4, 1944

